Most drugs may have deleterious effects. However, anticancer drugs are among those resulting in the worse adverse effects. Indeed, anticancer drugs are usually cytotoxic active agents with some preference for tumor cells. However, they also display some toxicity on other cells, thus resulting in often serious adverse reactions (20-25% of grade 3-4 toxicity and 0.2% mortality).
This is an important problem, since serious adverse effects not only affect patients' life quality, but may also result in death due to toxicity, or more often to the end or decrease of the treatment, thus decreasing its efficiency.
Interindividual metabolism variations, which influence drugs anabolism and catabolism capacities, participate to the toxicity risk. However, despite some recent improvements of the knowledge concerning anticancer drugs metabolism and of pharmacological technologies, therapeutic individualization is not yet common practice.
In contrast, doses are usually standardized. Although doses and protocols standardization may have been once useful, it now shows its limits concerning efficiency and toxicity of the treatment, depending on the treated subject.
However, the administered dose of anticancer drug is usually still calculated depending on body surface, which relevancy is based neither on experimental or theoretical justification, and at best on a few biological tests such as complete blood count and renal check-up. Individual pharmacokinetic, metabolic, genetic or epigenetic particularities are not taken into account.
There is thus a need for treatment methods using anticancer compounds in which such individual particularities would be taken into account in order to decrease toxicity and improve efficiency of the treatment.
5-fluorouracile (5-FU) is the leading anticancer drug of fluoropyrimidine family, a therapeutic class of agents interfering with DNA synthesis. 5-FU is a major chemotherapeutic drug, and is notably used in the treatment of colorectal cancer, gastric cancer, oesophagi cancer, ORL cancer, and breast cancer, particularly as an adjuvant treatment or in metastatic situations. Each year, more than 90 000 patients are treated by 5-FU.
However, 5-FU results in 20-25% of severe grade 3-4 toxicity, including toxicities in the digestive tract, such as diarrhea, which may be bloody or hemorrhagic; haematopoietic complications, such as leuco-neutropenias, which may result in superinfection or septicaemia; skin or mucosa complications, such as mucites, hand-foot syndrome; toxidermia; cardiac toxicity and a cerebellum syndrome.
Such adverse effects may be combined with each other, resulting in a polyvisceral toxicity scheme, with is very early in 5-8% of patients and even gives rise to death in 0.8% of treated patients. These adverse effects may also appear later, during the treatment.
5-FU is usually used in metastatic situations. In addition, it is also more and more often used as an adjuvant treatment, i.e. in the case of patients treated for a localized tumor for which a relapse is feared. The risk of a severe toxic adverse effect cannot be taken in such conditions.
The adverse effects of 5-FU are mainly due to a great interindividual variability of 5-FU metabolism. 5-FU cytotoxicity mechanism is based on its conversion in active nucleotides that block DNA synthesis. Such active nucleotides are obtained when 5-FU is metabolised by the anabolic pathway. However, there is an equilibrium between 5-FU enzymatic activation (anabolic pathway) and 5-FU elimination in the catabolic pathway. The initial and limiting enzyme of 5-FU elimination (catabolic pathway is dihydropyrimidine dehydrogenase (DPD). This ubiquitous enzyme is a major factor of 5-FU biodisponibility, since in a subject with normal DPD enzymatic activity, about 80% of administered 5-FU is eliminated by DPD in the catabolic pathway, while only 20% of administered 5-FU is available for the anabolic pathway that us necessary for its cytotoxic action.
However, in patients with a deficiency (total or partial) in DPD activity, the percentage of administered 5-FU that is available for the anabolic pathway that is necessary for its cytotoxic action is greatly increased, and these patients thus have an increased risk of developing acute, early and severe 5-FU toxicity.
On the other hand, in patient with an increased DPD activity a standard dose based on the body surface area is insufficient and consequently inefficient.
DPD activity shows a great interindividual variability, with measured activity values that may differ from a 6 times ratio between two distinct patients (Etienne M C, et al: J Clin Oncol 12: 2248-2253, 1994). This enzymatic variability results in a great variability in 5-FU metabolism and plasmatic kinetics, since 5-FU clearance varies of a factor 6 to 10 depending on the subject (Gamelin E., et al. J Clin Oncol, 1999, 17, 1105-1110; Gamelin E., et al. J. Clin. Oncol., 1998, 16 (4), 1470-1478).
This situation has enormous implications for treatment toxicity, but also for treatment efficiency. Indeed, several studies have shown that pharmacokinetic parameters are correlated with toxicity but also with treatment efficiency, notably concerning tumor response in colorectal and ORL cancers.
In addition, it has been found that the range of plasmatic 5-FU concentration in which the treatment is efficient and does not lead to severe adverse effects is rather narrow, so that there is not much difference between efficient and toxic plasmatic 5-FU concentrations.
There is thus a need for treatment methods that would take such variability into account in order to administer to each patient a 5-FU dose that will result in a plasmatic 5-FU concentration in the narrow range in which it is both sufficient to have therapeutic activity and is low enough to prevent severe grade 3-4 toxicities.
In addition to DPD activity variability, 5-FU metabolism also highly depends on the administered dose and mostly on administration duration, i.e. on perfusion duration. Indeed, DPD is saturable, so that a patient's plasmatic kinetics is not linear, and clearance is multiplied by a factor 10 when changing from a bolus administration to a continued perfusion during several hours or days (Gamelin E., Boisdron-Celle M. Crit Rev Oncol Hematol, 1999, 30, 71-79).
A general individual optimization method of 5-FU dose cannot thus be provided. In contrast, although some tolerance may apply for small variations, a particular individual optimization method of 5-FU dose has to be found for each 5-FU treatment protocol, depending on the dose and mostly duration of 5-FU administration.
In addition, the increase or decrease in 5-FU plasmatic concentration in a patient is not proportional to the increase or decrease of the dose of 5-FU that is administered to said patient, so that it is not easy to determine how much to increase or decrease the administered 5-FU dose in order to reach a particular 5-FU plasmatic concentration when starting from a higher or lower concentration obtained with a given administered 5-FU dose.
Moreover, although 5-FU was at some time used in monotherapies, it is now usually administered in combination with other cytotoxic agents, such as oxaliplatine or irinotecan, and optionally with additional targeted therapies using monoclonal antibodies, such as cetuximab, panitumumab or bevacizumab.
These additional agents, and particularly chemotherapeutic agents such as oxliplatin or irinotecan, may also generate adverse effects, which may be similar to those induced by 5-FU, thus creating a risk of synergism in toxicity development as well as in tumor treatment.
In particular, irinotecan may notably induce acute diarrhea, neutropenia and thrombopenia (Vanhoefer, U et al. J. Clin. Oncol., 19: 1501-1518, 2001).
As a result, depending on the chemotherapeutic agent that is used in combination with 5-FU, a particular individual optimization method of 5-FU dose has to be found. Such a method should determine the range in which the 5-FU plasmatic concentration is used.
Some attempts to optimize the 5-FU dose administered to patients in anticancer protocols have been made. However, as mentioned above, results are not transposable to other protocols, in particular if the administration mode (and notably the duration of the continuous infusion) of 5-FU is changed, or if 5-FU is combined with a chemotherapeutic agent that may influence 5-FU pharmacokinetics such as oxaliplatin.
Gamelin et al (Gamelin, E et al. J Clin Oncol. 2008 May 1; 26(13):2099-105) defined a method for adapting 5-FU dose in a treatment based on weekly administration of folinic acid combined with 5-FU in an 8 hours continuous infusion. However, such a protocol is no more used, since current protocols generally combine 5-FU with folinic acid and another chemotherapeutic drug, generally oxaliplatin or irinotecan. In addition, current protocols use much longer continuous infusions of 5-FU.
Ychou et al (Ychou M, Duffour J, Kramar A, et al. Cancer Chemother Pharmacol, 2003, 52: 282-90.) describe a method for increasing 5-FU dose in a treatment based on a bimonthly LV5FU2 regimen. However, such a protocol is also no more used, since current protocols generally combine 5-FU with folinic acid and another chemotherapeutic drug, generally oxaliplatin or irinotecan. In addition, the method described in Ychou et al only intends to increase the 5-FU dose, and an increase is systematically applied unless a significant (grade II-IV) toxicity is observed. Thus, although this method permits to increase the 5-FU dose and potentially to increase treatment efficiency, it does not permit to prevent severe toxicity by remaining in the narrow window in which 5-FU plasmatic levels are efficient but not toxic. The method of Ychou et al thus still make the patient take a significant risk, which is not acceptable in first line treatment.
In the present application, the inventors have found a method for optimizing the next 5-FU dose to be administered by continuous infusion to a patient treated with a FOLFIRI protocol (5-FU in bolus and continuous infusion of 46 hours, folinic acid, and irinotecan), based on the plasmatic 5-FU concentration measured from a blood sample taken before the end of the 5-FU perfusion, and on a new decision algorithm.